Alcohol (ethanol) abuse represents a major problem in our country with an estimated 14 million people being afflicted. To address this issue, scientists have begun to focus on medications development to prevent or treat alcoholism. However, the development of pharmacological treatments for alcoholism has not been very successful. This lack of success, in part, is due to the physical-chemical nature of ethanol's mechanism of action, which limits the ability to use standard pharmacological approaches to study ethanol's actions and effects and the ability to identify agents (antagonists) that can directly block ethanol at its site of action. My NRSA proposal builds on my mentor's NIAAA funded research showing that increased atmospheric pressure is a direct, mechanistic antagonist for ethanol that blocks and reverses a broad spectrum of ethanol's behavioral effects and ethanol's action on ligand-gated ion channels (LGICs) located in the CNS without causing changes in behavior or baseline receptor function. These qualities of pressure antagonism of ethanol hold out the possibility of developing therapeutic agents that can directly antagonize ethanol. However, we do not feel that pressure per se represents a viable therapeutic tool for treating alcoholism. My NRSA proposal represents the first initial step towards translating current knowledge regarding pressure antagonism of ethanol to the development of novel pharmacotherapeutic agents for treating alcoholism. The Specific Aim of this proposal focuses on identifying structural/functional mechanisms by which pressure acts to antagonize ethanol in Loop 2 of the extracellular domain of glycine receptors (GlyRs) and GABAARs - two important LGICs located in the CNS that have been linked to ethanol-induced behaviors. This will be accomplished by testing the hypothesis that physical-chemical parameters in the Loop 2 region in GlyRs and GABAARs play an important role in ethanol sensitivity and sensitivity to pressure antagonism of ethanol. The current proposal begins the process of identifying the mechanism of pressure antagonism of ethanol using hyperbaric, molecular, electrophysiological, pharmacological, computational chemistry and molecular modeling approaches. This work will contribute to our long-term goal of developing potential pharmacological agents that mimic pressure antagonism of ethanol. These agents will serve as prototypes for developing new pharmacotherapeutic treatments of alcoholism that act by antagonizing ethanol's action on molecular targets within CNS receptors. Finally, the studies that I have proposed in my NRSA application will provide me with valuable training and expertise and will significantly contribute to my development as an independent researcher in the alcohol field.